Receptors for the major brain excitatory and inhibitory neurotransmitters glutamate may play key roles in neural plasticities and are direct targets for abused drugs such as phencyclidine (PCP), barbiturates and benzodiazepines. Improved knowledge about this ligand gated ion channel family would thus enhance understanding of acute drug actions and, possibly, longer-term adaptive alterations that could underlie tolerance and dependence. During this FY, Addiction Research Center scientists and collaborators cloned several glutamate and NMDA receptor cDNAs, and a novel GABA receptor cDNA and gene. The novel glutamate receptor cDNAs, termed GluR5-3 and GluR6c, and the novel NMDA receptor cDNAs, NRlb and NRlc, each appear to represent subunit variants generated by alternative splicing of the respective transcripts. The novel GABA receptor, GABA rho2, is a close homolog of the interesting GABA rho1 cloned during the last FY. In several instances, these receptor variants are physiologically important. NMDAR1b mediates enhanced responsiveness to phorbol esters and altered sensitivity to polyamines. Several of these receptor genes have been mapped to mouse and human chromosomes. GABA rho2 forms a gene cluster with the GABA rho1 gene on human chromosome 6q. GluR5 maps near the familial amyotrophic lateral sclerosis locus on chromosome 21, and is thus a candidate gene for this disorder. Mapping the structure of the gene encoding KBP, one of the first glutamate receptor genes to be characterized, reveals that separate exons encode distinct KBP structural domains, and identifies several regulatory elements in its promoter region. These studies enhance understanding of the function of brain systems implicated in short-term responses to several abused drugs, and likely to play roles in long-term responses to all drugs.